• Asian Pacific Journal of Cancer Prevention
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• v.15 no.6
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• pp.2619-2623
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• 2014

Aim: To investigate signaling pathways for reversal of EGF-mediated multi-drug resistance (MDR) in hepatocellular carcinoma (HCC) models. Materials and Methods: HCC MDR cell strain HepG2/adriamycin (ADM) and SMMC7721/ADM models were established using a method of exposure to medium with ADM between low and high concentration with gradually increasing concentration. Drug sensitivity and reversal of multi-drug resistance by EGF were determined and the cell cycle distribution and apoptosis were analyzed by flow cytometry. Phosphorylation of ERK1, ERK2, ERK5 and expression of Bim were detected by Western blotting. Results: The results showed that HepG2/ADM and SMMC7721/ADM cells were resistant not only to ADM, but also to multiple anticancer drugs. When used alone, EGF had no anti-tumor activity in HepG2/ADM and SMMC7721/ADM cells in vitro, while it increased the cytotoxicity of ADM. EGF induced cell apoptosis and G0/G1 phase cell cycle arrest in HepG2/ADM And SMMC7721/ADM cells, while enhancing activity of p-ERKs and up-regulated expression of BimEL. Conclusions: EGF might enhance the chemosensitivity of HepG2/ADM and SMMC7721/ADM cells via up-regulating p-ERKs and BimEL protein.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4349-4352
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• 2016

Purpose: To evaluate whether combined transarterial chemoembolization (TACE) with radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) for hepatocellular carcinoma (HCC) have superior efficacy to transarterial chemoembolization (TACE) alone a retrospective review was conducted. Methods: During January 2009 to March 2013, 108 patients with hepatocellular carcinoma underwent TACE or combined therapies (TACE+RFA or TACE+PEI). The long-term survival rates were evaluated in those patients by various statistical analyses. Results: The cumulative survival rates in the combined TACE+RFA/PEI group were significantly superior to those in the TACE alone group. When the comparison among the groups was restricted to patients with two or three tumors fulfilling the Milan criteria, significantly greater prolongation of survival was observed in the combined TACE+ RFA/PEI group than in the RFA/PEI alone group. Conclusions: In terms of the effect on the survival period, combined TACE+ RFA/PEI therapy was more effective than TACE monotherapy, and also more effective than PEI or RFA monotherapy in cases with multiple tumors.

• BMB Reports
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• v.55 no.11
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• pp.547-552
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• 2022

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7101-7106
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• 2013

Background: The prognosis of patients with hepatocellular carcinoma (HCC) after curative resection varies greatly. Few studies had investigated the risk factors for early recurrence (recurrence-free time ${\leq}$ 1 year) of hepatitis B virus (HBV)-related HCCs meeting Milan criteria. Methods: A retrospective analysis was performed on the 224 patients with HCC meeting Milan criteria who underwent curative liver resection in our center between February 2007 and March 2012. The overall survival (OS) rate, recurrence-free survival (RFS) rate and risk factors for early recurrence were analyzed. Results: After a median follow-up of 33.3 months, HCC reoccurred in 105 of 224 patients and 32 died during the period. The 1-, 3- and 5-year OS rates were 97.3%, 81.6% and 75.6% respectively, and the 1-, 3- and 5-year RFS rates were 73.2%, 53.7% and 41.6%. Cox regression showed alpha-fetoprotein (AFP) > 800 ng/ml (HR 2.538, 95% CI 1.464-4.401, P=0.001), multiple tumors (HR 2.286, 95% CI 1.123-4.246, P=0.009) and microvascular invasion (HR 2.518, 95% CI 1.475-4.298, P=0.001) to be associated with early recurrence (recurrence-free time ${\leq}$ 1-year) of HCC meeting Milan criteria. Conclusions: AFP > 800 ng/ml, multiple tumors and microvascular invasion are independent risk factors affecting early postoperative recurrence of HCC. In addition resection appears capable of replacing liver transplantation in some situations with safety and a better outcome.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.1649-1654
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• 2013

Objective: This work aimed to evaluate the safety and clinical efficacy of transcatheter arterial chemoembolization (TACE) combined with c-arm cone-beam CT guided synchronous radiofrequency ablation (RFA) in treatment of large hepatocellular carcinoma (HCC). Methods: 21 patients with large HCC were studied from January 2010 to March 2012. TACE combined with synchronous C-arm cone-beam CT guided RFA were performed on a total of 25 lesions. Conventional imaging examination (CEUS, enhanced CT or MRI) and AFP detection were regularly conducted to evaluate the technical success rate of combined treatment, complications, treatment response, time without disease recurrence and survival rate. Results: The technical success rate of combined treatment was 100%, without any significant complication. After 1 month, there were 19 cases with complete response and 2 cases with partial response, with an complete response rate of 90.4% (19/21) and a clinical effective rate of 100% (21/21). The complete response rates of single nodular lesions (100%, 17/17) was significantly higher than that of multiple nodular lesions (50%, 2/4) (P<0. 05). During 2 to 28 months of follow-up, in 19 cases with complete response, the average time without disease recurrence was $10.8{\pm}6$ months. The total survival rates of 6, 12 and 18 months in 21 patients were 100%, respectively. Conclusion: TACE combined with synchronous C-arm CT guided RFA is safe and effective for treatment of large HCC. The treatment efficacy for single nodular lesion is better than that for multiple nodular lesions.

• Genomics & Informatics
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• v.7 no.4
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• pp.195-202
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• 2009

BIRC5 (Survivin) belongs to the inhibitor of apoptosis gene family. The BIRC5 protein inhibits caspases and consequently blocks apoptosis. Thus, BIRC5 contributes to the progression of cancer allowing for continued cell proliferation and survival. In this study, we identified eight sequence variants of BIRC5 through direct DNA sequencing. Among the eight single nucleotide polymorphisms (SNPs), six common variants with frequencies higher than 0.05 were selected for larger-scale genotyping (n=1,066). Results of the study did not show any association between the promoter region polymorphisms and the clearance of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) occurrence. This is in line with a previous study in which polymorphisms in the promoter region does not influence the function of BIRC5. Initially, we were able to detect a signal with the ＋9194A>G, which disappeared after multiple corrections but led to a change in amino acid. Similarly, we were also able to detect an association signal between two haplotypes (haplotype-2 and haplotype-5) on the onset age of HCC and/or HCC occurrence, but the signals also disappeared after multiple corrections. As a result, we concluded that there was no association between BIRC5 polymorphisms and the clearance HBV infection and/or HCC occurrence. However, our results might useful to future studies.

• Nuclear Medicine and Molecular Imaging
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• v.42 no.5
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• pp.414-418
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• 2008

The role of positron emission tomography (PET) with F-18 fluorodeoxyglucose (F-18 FDG) in the diagnosis of hepatocellulcar carcinoma (HCC) has been limited because of a variable FDG uptake in HCC. However, the usefulness of PET/CT for detecting extrahepatic metastasis and monitoring of the treatment response in HCC has been reported. A 55-year-old man with a hepatitis B surface antigen-positive, was admitted to our hospital due to dyspnea, general weakness and body weight loss for one month. Chest X-ray showed multiple reticulo-nodular densities on both lower lung fields, which implies metastatic lesions. F-18 FDG PET/CT revealed consecutively intense hypermetabolic mass in right hepatic lobe, inferior vena cava and right atrium. We report a case of HCC with IVC and right atrium invasion identified by F-18 FDG PET/CT.

• Communications for Statistical Applications and Methods
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• v.25 no.4
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• pp.385-396
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• 2018

Competing risks are commonly encountered in biomedical research. Regression models for competing risks data can be developed based on data routinely collected in hospitals or general practices. However, these data sets usually contain the covariate missing values. To overcome this problem, multiple imputation is often used to fit regression models under a MAR assumption. Here, we introduce a multivariate imputation in a chained equations algorithm to deal with competing risks survival data. Using pseudo-observations, we make use of the available outcome information by accommodating the competing risk structure. Lastly, we illustrate the practical advantages of our approach using simulations and two data examples from a coronary artery disease data and hepatocellular carcinoma data.

• Tuberculosis and Respiratory Diseases
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• v.62 no.4
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• pp.318-322
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• 2007

Although reports of multiple primary malignant tumors have increased recently, cases of synchronous double primary tumors of lung and liver are rare. A 73-year-old man suffered from chronic cough. His chest x-ray showed segmental atelectasis of the right upper lobe. Bronchoscopy revealed a mass occluding the orifice of the anterior segmental bronchus of the right upper lobe, and a biopsy showed a squamous cell carcinoma. A synchronous hepatic mass was found by ultrasonography. However, F18-FDG-PET showed no evidence of a distant metastasis. The liver biopsy revealed a hepatocellular carcinoma. A right upper lobe lobectomy and a sleeve resection were performed for the lung cancer, and radiofrequency ablation was performed for the hepatocellular carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3151-3156
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• 2014

Background: Sorafenib is a promising drug for advanced hepatocellular carcinoma (HCC); however, treatment may be discontinued for multiple reasons, such as progressive disease, adverse events, or the cost of treatment. The consequences of sorafenib discontinuation and continuation are uncertain. Materials and Methods: We retrospectively analyzed 88 HCC patients treated with sorafenib from July 2007 to January 2013. Overall survival (OS), post-disease progression overall survival (pOS), and time to disease progression (TTP) were compared for survival analysis. Cox proportional hazard regression was performed to assess the effect of important factors on OS in the overall patient population and on pOS in patients who continued sorafenib treatment. Results: Sorafenib was discontinued and continued in 24 and 64 patients, respectively. The median OS (355 vs 517 days respectively; p=0.015) and median post-PD OS (260 vs 317 days, respectively; p=0.020) were statistically different between the discontinuation and continuation groups. Neither the median time to first PD nor the time to second PD were significantly different between the 2 groups. In the discontinuation group, 3 of the 24 patients (12.5%) suffered disease outbreaks. In Cox proportional hazard regression analysis after correction for confounding factors, BCLC stage (p=0.002) and PD site (p=0.024) were significantly correlated with pOS in patients who continued sorafenib treatment. Conclusions: Sorafenib discontinuation may cause HCC flares or outbreaks. It is advisable to continue sorafenib treatment after first PD, particularly in patients with Barcelona Clinic Liver Cancer stage B disease or only intrahepatic PD.